Although it was considered that sphingosine-1-phosphate (S1P) was only an intermediate metabolite in sphingosine metabolism, it has been reported that S1P has a cell growth stimulatory activity and a control action of cell movement function. Thus, it is becoming clear that S1P is a new lipid mediator which demonstrates a variety of physiological functions, such as an apoptotic activity, cell morphology regulatory action, and vasoconstriction (Non-patent Documents 1 and 2). Although this lipid has two actions, as an intracellular second messenger and as an intercellular mediator, research concerning its action as an intercellular mediator is especially active. It has been reported that signaling is carried out via a plurality of G protein-conjugated receptors (Endothelial Differentiation Gene, EDG) which are present on the cell membrane surface (Non-patent Documents 1 and 3). Currently, five S1P receptor subtypes are known, Edg-1, Edg-3, Edg-5, Edg-6, and Edg-8, which are respectively referred to as S1P1, S1P3, S1P2, S1P4, and S1P5.
From the various research concerning these S1P receptors, it has been reported that a so-called S1P receptor modulator, which exhibits an agonistic activity or an antagonistic activity against such receptors, demonstrates effectiveness against a wide variety of diseases. For example, it has been disclosed that a compound which acts on Edg-5 (S1P2) is effective against arteriosclerosis, renal fibrosis, hepatic fibrosis, and hepatic fibrosis (Patent Document 1). Furthermore, it has been disclosed that a compound which acts on Edg-1 (S1P1), Edg-3 (S1P3), or Edg-5 is effective as a treatment and a preventive agent for respiratory illnesses such as chronic bronchial asthma, diffuse pulmonary hamartoangiomyomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), pneumonitis, idiopathic interstitial pneumonia, lung cancer, and pneumonia hypersensitivity (Patent Document 2). Furthermore, it has been disclosed that a compound which has an Edg-1 agonistic activity is effective as a treatment and a preventive agent for arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease, diabetic neuropathy peripheral arterial disease, septicemia, angiitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous state, arteriosclerosis, varices such as hemorrhoids, anal fissures, and anal fistula, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, bedsores, burns, ulcerative colitis, Crohn's disease, heart transplantation, kidney transplantation, skin grafts, liver transplantation, bone marrow transplantation, bone loss, chronic hepatitis, liver cirrhosis, chronic renal failure, and focal glomerular sclerosis (Patent Document 3).
Furthermore, it has been reported that compounds having an S1P receptor agonistic activity regulate leukocyte migration (Non-patent Documents 4 and 5). It has also been disclosed that, in addition to being effective for various organ transplants and GVHD, the series of derivatives introduced in these Non-patent documents are effective for rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, type I and II diabetes mellitus, autoimmune diseases such as Crohn's disease, allergic diseases such as atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and allergic contact dermatitis, and inflammatory diseases such as inflammatory bowel disease or ulcerative colitis (Non-patent Documents 4 and 5). Furthermore, a phosphate derivative analogous to what is disclosed in Non-patent Documents 4 and 5 has also been disclosed as an S1P receptor antagonist (Non-patent Document 6). Recently, various compounds, such as amino alcohol derivatives, phosphate derivatives, and carboxylate derivatives, have been disclosed as S1P1 to S1P5 receptor modulators focused on S1P1 receptors, or as immunosuppressive agents (Patent Documents 7 to 62).
Furthermore, since S1P4 receptors are largely concentrated in immunocompetent cells, such as leukocytes, and in organs which greatly contribute to the immune system, it is suggested that S1P4 receptors have a strong contribution to the immune system. In fact, compounds having an S1P4 agonistic activity have been disclosed for autoimmune diseases such as SLE and rheumatism, asthma, allergic diseases such as atopic dermatitis, and inflammatory disease remedies (Patent Documents 30, 35, and 46).
Thus, while a great deal of attention is being paid to S1P receptor agonist drugs which may have hidden potential in a wide variety of medical applications, not all S1P receptor agonist drugs provide a desirable action on the body.
For example, an S1P receptor agonist which has exhibited effectiveness in clinical trials in suppressing organ transplant rejection was found to produce bradycardia as a side effect after administration. This effect was reported to probably be caused by agonistic activity against the S1P3 receptor (Non-patent Documents 6 and 7). Furthermore, agonistic activity against the S1P3 receptor has also been reported to obstruct myocardial blood flow (Non-patent Document 8), and cause cerebral arterial spasms (Non-patent Document 9), and pulmonary edema (Non-patent Document 10).    [Patent Document 1] WO 0198301 pamphlet    [Patent Document 2] WO 03020313 pamphlet    [Patent Document 3] WO 02092068 pamphlet    [Patent Document 4] WO 0218395 pamphlet    [Patent Document 5] WO 02076995 pamphlet    [Patent Document 6] Japanese Patent Application Laid-Open No. 2003-137894    [Patent Document 7] WO 03040097 pamphlet    [Patent Document 8] WO 02064616 pamphlet    [Patent Document 9] WO 02062389 pamphlet    [Patent Document 10] Japanese Patent Application Laid-Open No. 2002-316985    [Patent Document 11] Japanese Patent Application Laid-Open No. 2003-267936    [Patent Document 12] WO 03051876 pamphlet    [Patent Document 13] WO 03061567 pamphlet    [Patent Document 14] WO 03062248 pamphlet    [Patent Document 15] WO 03062252 pamphlet    [Patent Document 16] WO 03073986 pamphlet    [Patent Document 17] WO 03074008 pamphlet    [Patent Document 18] WO 03105771 pamphlet    [Patent Document 19] WO 04010949 pamphlet    [Patent Document 20] WO 04024673 pamphlet    [Patent Document 21] WO 04058149 pamphlet    [Patent Document 22] WO 04071442 pamphlet    [Patent Document 23] WO 04096752 pamphlet    [Patent Document 24] WO 04096757 pamphlet    [Patent Document 25] WO 04103279 pamphlet    [Patent Document 26] WO 04103306 pamphlet    [Patent Document 27] WO 04103309 pamphlet    [Patent Document 28] WO 04110979 pamphlet    [Patent Document 29] WO 04113330 pamphlet    [Patent Document 30] WO 04074297 pamphlet    [Patent Document 31] WO 05014603 pamphlet    [Patent Document 32] WO 05020882 pamphlet    [Patent Document 33] WO 04002531 pamphlet    [Patent Document 34] WO 05032465 pamphlet    [Patent Document 35] WO 05041899 pamphlet    [Patent Document 36] WO 05058848 pamphlet    [Patent Document 37] WO 05070886 pamphlet    [Patent Document 38] WO 05082089 pamphlet    [Patent Document 39] WO 05082841 pamphlet    [Patent Document 40] WO 05021503 pamphlet    [Patent Document 41] WO 05040091 pamphlet    [Patent Document 42] WO 05085179 pamphlet    [Patent Document 43] WO 05118523 pamphlet    [Patent Document 44] WO 05014525 pamphlet    [Patent Document 45] WO 06020951 pamphlet    [Patent Document 46] WO 06001463 pamphlet    [Patent Document 47] WO 03029184 pamphlet    [Patent Document 48] WO 03029205 pamphlet    [Patent Document 49] WO 04026817 pamphlet    [Patent Document 50] WO 04074297 pamphlet    [Patent Document 51] WO 05021503 pamphlet    [Patent Document 52] Japanese Patent Application Laid-Open No. 2004-307439    [Patent Document 53] Japanese Patent Application Laid-Open No. 2004-307440    [Patent Document 54] Japanese Patent Application Laid-Open No. 2004-307441    [Patent Document 55] Japanese Patent Application Laid-Open No. 2004-307442    [Patent Document 56] WO 06041015 pamphlet    [Patent Document 57] Japanese Patent Application Laid-Open No. 2004-137208    [Patent Document 58] Japanese Patent Application Laid-Open No. 2005-41867    [Patent Document 59] Japanese Patent Application Laid-Open No. 2005-47899    [Patent Document 60] WO 05040091 pamphlet    [Patent Document 61] WO 05063671 pamphlet    [Patent Document 62] WO 05079788 pamphlet    [Non-patent Document 1] Y. Takuma et al., Mol. Cell. Endocrinol., 177, 3 (2001).    [Non-patent Document 2] Y. Igarashi, Ann, N.Y. Acad. Sci., 845, 19 (1998).    [Non-patent Document 3] H. Okazaki et al., Biochem. Biophs. Res. Commun., 190, 1104 (1993).    [Non-patent Document 4] S. Mandala et al., Science, 296, 346 (2002).    [Non-patent Document 5] V. Brinkmann et al., J. Biol. Chem., 277 and 21453 (2002).    [Non-patent Document 6] M. G. Sanna et al., J. Biol. Chem., 279, 13839 (2004).    [Non-patent Document 7] M. Forrest et al., J. Pharmacol. Exp. Ther., 309, 758 (2004).    [Non-patent Document 8] B. Levkau et al., Circulation, 110, 3358 (2004).    [Non-patent Document 9] S. Salomone et al., Eur. J. Pharmacol. 469, 125 (2003).    [None-patent Document 10] Y. Gon et al., PNAS 102, 9270 (2005).